General MM

Panobinostat works synergistically with daratumumab by up-regulating CD38

Panobinostat is a HDAC inhibitor used to treat multiple myeloma (MM) and effects expression of several critical genes. The question of its mechanism of action on myeloma cells was addressed in a letter to the editor of Blood, published in May 2017. Estefania Garcia-Guerrero and colleagues from Medizinische Klinik and Poliklinik II, University of Würzburg, Germany, and Institute of Biomedicine Seville, IBIS Hospital, University of Seville, Spain, showed that panobinostat specifically up-regulates CD38 on MM cells and that this increase augments the effect of the monoclonal antibody daratumumab.

Key Findings:

Up-regulation of CD38:

  • Uniform increase in CD38 was observed on primary myeloma cells (n= 12 patients) in response to panobinostat titration (0-25 nM)
  • Expression increased after 24 hrs with a peak at 48 hrs
  • Mean Fluorescence Intensity (MFI) was 3 fold (10nM) and 5-fold (25nM) higher than untreated myeloma at 48 hrs (p<0.01)
  • CD38 up-regulation was uniform across patients (pts) with newly diagnosed MM (n=5), relapsed and refractory MM (RRMM) (n=7)
  • Enhanced expression was confirmed in two MM cell lines – MM1.S and OPM-2
  • CD38 levels returned to baseline 24 hrs after withdrawal of panobinostat; re-exposure increased CD38 to comparable levels
  • The effect was myeloma cell specific; no increase in CD38 on other lymphoma cell lines

Synergy with daratumumab:

  • Primary myeloma cells (n=4 patients) were treated with panobinostat for 48 hours at 10 nM
  • Daratumumab or control antibody was then added, along with patient-derived autologous PBMC
  • Significant increase in ADCC (4 hr assay) observed for panobinostat treated vs untreated cells
  • Percentage of panobinostat-treated primary myeloma cells eliminated by daratumumab = 78% vs 51% without panobinostat treatment (p<0.01)
  • This effect was confirmed with the MM1.S myeloma cell line (panobinostat-treated vs untreated plus daratumumab): after 4 hours = 45% vs 26%; after 20 hrs: 89% vs 64%; (n=3 experiments, p<0.0001)
  • This effect primarily occurs via antibody dependent cell-mediated cytotoxicity (ADCC); no complement dependent cytotoxicity (CDC) was observed
  • CD38 up-regulation was not observed across other cell types (eg. T cells), indicating specificity for myeloma cells

In conclusion, the ability of panobinostat to selectively up-regulate CD38 on myeloma cells provided a synergistic effect when administered with daratumumab, and warrants further investigation of this dual treatment regimen.

References
  1. García-Guerrero E. et al. Panobinostat induces CD38 upregulation and augments the anti-myeloma efficacy of daratumumab. Blood. 2017 May 5. pii: blood-2017-03-770776. DOI: 10.1182/blood-2017-03-770776. [Epub ahead of print]
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